A Nonlinear ODE Model of Tumor Growth and Effect of Immunotherapy and Chemotherapy Treatment in Colorectal Cancer

Colorectal cancer will kill approximately 50,000 people in the United States this year. Current treatment options, including surgery, chemotherapy, and radiation, are often able to force the cancer into remission, but better treatments are needed to help those who don\u27t respond to current treatments. A new and promising treatment option, monoclonal-antibody therapy, has the potential to help reduce the deaths caused by colorectal cancer, but most monoclonal-antibody drugs are currently still in trial phases, and the variations in the dosing schedule of those currently approved for use have not been heavily explored. We have modified a nonlinear ODE tumor/treatment model by de Pillis and colleagues to include monoclonal antibody treatments. Parameter values have been modified for colorectal cancer, with irinotecan as the chemotherapy agent and the two monoclonal antibodies cetuximab, which is FDA approved, and panitumumab, which is still undergoing clinical trials. We have run Matlab simulations of current treatment options, and have found new dosing schedules which, in our simulations, reduce tumor size more effectively that the current schedules. Equilibria of the system and its sensitivity to parameters have also been examined

TLR induces reorganization of the IgM-BCR complex regulating murine B-1 cell responses to infections.

In mice, neonatally-developing, self-reactive B-1 cells generate steady levels of natural antibodies throughout life. B-1 cells can, however, also rapidly respond to infections with increased local antibody production. The mechanisms regulating these two seemingly very distinct functions are poorly understood, but have been linked to expression of CD5, an inhibitor of BCR-signaling. Here we demonstrate that TLR-mediated activation of CD5+ B-1 cells induced the rapid reorganization of the IgM-BCR complex, leading to the eventual loss of CD5 expression, and a concomitant increase in BCR-downstream signaling, both in vitro and in vivo after infections of mice with influenza virus and Salmonella typhimurium. Both, initial CD5 expression and TLR-mediated stimulation, were required for the differentiation of B-1 cells to IgM-producing plasmablasts after infections. Thus, TLR-mediated signals support participation of B-1 cells in immune defense via BCR-complex reorganization

The Effect of Aerobic Exercise on Tumor Hypoxia and Metabolism in a Murine Melanoma Model

https://openworks.mdanderson.org/sumexp21/1187/thumbnail.jp

Earthquake slip surfaces identified by biomarker thermal maturity within the 2011 Tohoku-Oki earthquake fault zone.

Extreme slip at shallow depths on subduction zone faults is a primary contributor to tsunami generation by earthquakes. Improving earthquake and tsunami risk assessment requires understanding the material and structural conditions that favor earthquake propagation to the trench. We use new biomarker thermal maturity indicators to identify seismic faults in drill core recovered from the Japan Trench subduction zone, which hosted 50 m of shallow slip during the Mw9.1 2011 Tohoku-Oki earthquake. Our results show that multiple faults have hosted earthquakes with displacement ≥ 10 m, and each could have hosted many great earthquakes, illustrating an extensive history of great earthquake seismicity that caused large shallow slip. We find that lithologic contrasts in frictional properties do not necessarily determine the likelihood of large shallow slip or seismic hazard

Blimp-1-dependent and -independent natural antibody production by B-1 and B-1-derived plasma cells.

Natural antibodies contribute to tissue homeostasis and protect against infections. They are secreted constitutively without external antigenic stimulation. The differentiation state and regulatory pathways that enable continuous natural antibody production by B-1 cells, the main cellular source in mice, remain incompletely understood. Here we demonstrate that natural IgM-secreting B-1 cells in the spleen and bone marrow are heterogeneous, consisting of (a) terminally differentiated B-1-derived plasma cells expressing the transcriptional regulator of differentiation, Blimp-1, (b) Blimp-1+, and (c) Blimp-1neg phenotypic B-1 cells. Blimp-1neg IgM-secreting B-1 cells are not simply intermediates of cellular differentiation. Instead, they secrete similar amounts of IgM in wild-type and Blimp-1-deficient (PRDM-1ΔEx1A) mice. Blimp-1neg B-1 cells are also a major source of IgG3. Consequently, deletion of Blimp-1 changes neither serum IgG3 levels nor the amount of IgG3 secreted per cell. Thus, the pool of natural antibody-secreting B-1 cells is heterogeneous and contains a distinct subset of cells that do not use Blimp-1 for initiation or maximal antibody secretion

Pengaruh Jus Buah Nanas (Ananas Comosus (L.) Merr.) Terhadap Profil Farmakokinetik Parasetamol Pada Tikus Putih Jantan (Rattus Norvegicus) Galur Wistar

Obat yang digunakan bersamaan dengan makanan atau minuman dapatmempengaruhi efek terapi obat tersebut. Penelitian ini dilakukan untuk mengetahuipengaruh jus buah nanas (Ananas comosus (L.) Merr.) terhadap profil farmakokinetikparasetamol pada tikus putih jantan galur Wistar. Hewan uji dikelompokkan secara acakdibagi menjadi 3 kelompok. Kelompok I (parasetamol) diberikan parasetamol tunggaldosis 9 mg/200gBB peroral. Kelompok II (parasetamol dan jus nanas dosis 1) diberikanparasetamol dosis 9 mg/200gBB bersamaan dengan jus buah nanas dosis 2,7 g/200gBB.Kelompok III (parasetamol dan jus nanas dosis 2) diberikan parasetamol dosis 9mg/200gBB bersamaan dengan jus buah nanas dosis 5,4 g/200gBB. Cuplikan darahhewan uji diambil selama 9 jam pada vena lateralis ekor tikus. Penetapan kadarparasetamol pada plasma dilakukan dengan spektrofotometer UV. Parameterfarmakokinetik dihitung menggunakan metode regresi linear dan metode residualselanjutnya diuji secara statistik menggunakan One Way ANOVA dengan tingkatkepercayaan 95%. Berdasarkan hasil penelitian memperlihatkan bahwa kelompok II dankelompok III meningkatkan secara signifikan parameter Cpmaks, t, tab, tel, AUCdan menurunkan secara signifikan parameter ka, ke, dan CL. Kelompok III memberikanpengaruh yang paling kuat terhadap profil farmakokinetik parasetamol yaitu denganmenurunkan parameter absorbsi dan eliminasi serta meningkatkan parametermetabolisme parasetamol pada tikus

Neural mediators of subjective and autonomic responding during threat learning and regulation

Threat learning elicits robust changes across multiple affective domains, including changes in autonomic indices and subjective reports of fear and anxiety. It has been argued that the underlying causes of such changes may be dissociable at a neural level, but there is currently limited evidence to support this notion. To address this, we examined the neural mediators of trial-by-trial skin conductance responses (SCR), and subjective reports of anxious arousal and valence in participants (n = 27; 17 females) performing a threat reversal task during ultra-high field functional magnetic resonance imaging. This allowed us to identify brain mediators during initial threat learning and subsequent threat reversal. Significant neural mediators of anxious arousal during threat learning included the dorsal anterior cingulate, anterior insula cortex (AIC), and ventromedial prefrontal cortex (vmPFC), subcortical regions including the amygdala, ventral striatum, caudate and putamen, and brain-stem regions including the pons and midbrain. By comparison, autonomic changes (SCR) were mediated by a subset of regions embedded within this broader circuitry that included the caudate, putamen and thalamus, and two distinct clusters within the vmPFC. The neural mediators of subjective negative valence showed prominent effects in posterior cortical regions and, with the exception of the AIC, did not overlap with threat learning task effects. During threat reversal, positive mediators of both subjective anxious arousal and valence mapped to the default mode network; this included the vmPFC, posterior cingulate, temporoparietal junction, and angular gyrus. Decreased SCR during threat reversal was positively mediated by regions including the mid cingulate, AIC, two sub-regions of vmPFC, the thalamus, and the hippocampus. Our findings add novel evidence to support distinct underlying neural processes facilitating autonomic and subjective responding during threat learning and threat reversal. The results suggest that the brain systems engaged in threat learning mostly capture the subjective (anxious arousal) nature of the learning process, and that appropriate responding during threat reversal is facilitated by participants engaging self- and valence-based processes. Autonomic changes (SCR) appear to involve distinct facilitatory and regulatory contributions of vmPFC sub-regions

Both B-1a and B-1b cells exposed to Mycobacterium tuberculosis lipids differentiate into IgM antibody-secreting cells

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. The cellular immune response to mycobacteria has been characterized extensively, but the antibody response remains underexplored. The present study aimed to examine whether host or bacterial phospholipids induce secretion of IgM, and specifically anti-phospholipid IgM, antibodies by B cells and to identify the responsible B-cell subset. Here we show that peritoneal B cells responded to lipid antigens by secreting IgM antibodies. Specifically, stimulation with M. tuberculosis H37Rv total lipids resulted in significant induction of total and anti-phosphatidylcholine IgM. Similarly, IgM antibody production increased significantly with stimulation by whole Mycobacterium bovis bacillus Calmette–Guerin. The B-1 subset was the dominant source of IgM antibodies after exposure to cardiolipin. Both CD5+ B-1a and CD5 B-1b cell subsets secreted total IgM antibodies after exposure to M. tuberculosis H37Rv total lipids in vitro. Overall, our results suggest that the poly-reactive B-1 cell repertoire contributes to non-specific anti-phospholipid IgM antibody secretion in response to M. tuberculosis lipids.Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. The cellular immune response to mycobacteria has been characterized extensively, but the antibody response remains underexplored. The present study aimed to examine whether host or bacterial phospholipids induce secretion of IgM, and specifically anti-phospholipid IgM, antibodies by B cells and to identify the responsible B-cell subset. Here we show that peritoneal B cells responded to lipid antigens by secreting IgM antibodies. Specifically, stimulation with M. tuberculosis H37Rv total lipids resulted in significant induction of total and anti-phosphatidylcholine IgM. Similarly, IgM antibody production increased significantly with stimulation by whole Mycobacterium bovis bacillus Calmette–Guerin. The B-1 subset was the dominant source of IgM antibodies after exposure to cardiolipin. Both CD5+ B-1a and CD5 B-1b cell subsets secreted total IgM antibodies after exposure to M. tuberculosis H37Rv total lipids in vitro. Overall, our results suggest that the poly-reactive B-1 cell repertoire contributes to non-specific anti-phospholipid IgM antibody secretion in response to M. tuberculosis lipids

Dissecting task-based fMRI activity using normative modelling: an application to the Emotional Face Matching Task

Functional neuroimaging has contributed substantially to understanding brain function but is dominated by group analyses that index only a fraction of the variation in these data. It is increasingly clear that parsing the underlying heterogeneity is crucial to understand individual differences and the impact of different task manipulations. We estimate large-scale (N = 7728) normative models of task-evoked activation during the Emotional Face Matching Task, which enables us to bind heterogeneous datasets to a common reference and dissect heterogeneity underlying group-level analyses. We apply this model to a heterogenous patient cohort, to map individual differences between patients with one or more mental health diagnoses relative to the reference cohort and determine multivariate associations with transdiagnostic symptom domains. For the face>shapes contrast, patients have a higher frequency of extreme deviations which are spatially heterogeneous. In contrast, normative models for faces>baseline have greater predictive value for individuals’ transdiagnostic functioning. Taken together, we demonstrate that normative modelling of fMRI task-activation can be used to illustrate the influence of different task choices and map replicable individual differences, and we encourage its application to other neuroimaging tasks in future studies

Corrigendum: p90RSK-MAGI1 Module Controls Endothelial Permeability by Post-translational Modifications of MAGI1 and Hippo Pathway.

[This corrects the article DOI: 10.3389/fcvm.2020.542485.]